The release of different transmitters, peptides and hormones represent a fundamental distinction among neuron types as they produce categorically different outputs that elicit distinct physiological actions in target cells. We revealed a neuropeptide code of GABAergic neurons. Over 30 neuropeptides, hormones and secreted ligands are expressed in over 50% of single cells of the PCPs, and each expresses ~3–10 different endogenous ligands (Figure 6B, S6A); individual neurons express multiple peptide and protein ligands (Figure 6C). Importantly, differential expression of these ligands is the most discriminating gene family for PCPs (AUROC=0.96). Multiple PCPs are uniquely marked by individual ligands (Figure 6B–C; e.g. CHC: Pthlh, PV: Tac1, Adm, NOS1/SST: Ptn, Rln1, CR/SST: Nppc, VIP/CCK: Edn3, Pnoc). These results indicate that, beyond their morpho-physiological differences, PCPs are different neuroendocrine cells that produce distinct chemical outputs and elicit distinct physiological effects. Consistent with the demand for processing and packaging diverse neuropeptides, the granin gene family, which regulates pre-prohormone cleavage and biogenesis of DCVs, also shows differential expression (AUROC=0.81; Table S4). Further, based on the role Pleiotropin (PTN) in axon myelination and its exclusive expression in NOS1/SST cells, we discovered that the axons of these long projection GABAergic neurons are myelinated (Figure S6B–G).
